Sustained expression of liver-specific function by hepatocytes in culture requires a basement membrane-like matrix as the culture substratum. Individual components of the matrix cannot substitute for the complex. The implications of these findings for the intact liver include the possibility that the extracellular matrix helps maintain normal parenchymal cell function and that alteration of the matrix underlies the loss of hepatocellular function that occurs in acute inflammation. Moreover, the low level of DNA synthesis by hepatocytes on the complex substratum, in contrast to that of cells cultured on collagen, suggests that extracellular matrix also modulates hepatocyte proliferation.